Genetic Testing in Clinical Medicine and Eye Care

As advances in technology arise, so do the number of identified conditions that have a genetic etiology, as well as the variety of genetic tests available. Between 2012 and 2022, the cumulative frequency of genetic testing in the United States skyrocketed from 197 tests to 37,271 tests, with a large majority being used for diagnostic purposes.¹ The American Academy of Ophthalmology Task Force on Genetic Testing previously established standards in 2012, revised in 2014, for how eyecare providers should approach genetic testing for their patients.² These standards address appropriate use of genetic testing, including patient selection and clinical indications. Genetic testing is particularly useful in eye care, as many ocular conditions, such as Best disease and pattern dystrophies, can present similarly, increasing the risk of misdiagnosis. Here’s how you can utilize genetic testing in practice.

ACQUIRE A THOROUGH HISTORY/EXAMINATION

A suspicious family history and overlapping or atypical clinical findings can indicate genetic testing for diagnostic confirmation (see “Case in Point”). Common conditions that eyecare providers may test for include, but are not limited to:

• Inherited retinal diseases, such as retinitis pigmentosa, Leber congenital amaurosis, Stargardt disease, Best disease, and oculocutaneous albinism.

• Corneal dystrophies, such as endothelial dystrophy, macular dystrophy, and amyloidosis.

• Various types of glaucoma, including congenital glaucoma and primary open-angle glaucoma.

IDENTIFY A TESTING ORGANIZATION

The National Library of Medicine’s National Center for Biotechnology Information offers a Genetic Testing Registry at ncbi.nlm.nih.gov/gtr. Specifically, it is a resource designed to assist healthcare providers in both finding and comparing genetic, genomic, serologic, and molecular tests. Searches can be by condition, laboratory, test name, and test target. As an example, when inputting Stargardt disease (FFM), 10 genetic tests from seven labs populate a list. Specific labs relevant to eyecare providers that may present in the registry include Labcorp Genetics, BluePrint Genetics, and PreventionGenetics. Some organizations like Seonix Bio use third-party labs that are not specifically on the registry but are available for testing.

Eyecare providers must register with genetic testing programs to order tests and submit relevant patient information for testing. As with many areas of health care, cost of genetic testing can be a significant barrier for patients. When possible, testing organizations will work with a patient’s health insurance to maximize coverage and limit out-of-pocket costs. One way to expand access is through sponsored testing programs. The following programs are available: the My Retina Tracker Genetic Testing Program, Invitae Unlock Inherited Retinal Disorders Panel, Scout Early-Onset Bilateral Cataracts Sponsored Testing Program, and the Scout PBD-ZSD Testing Program.

Case in Point

A 64-year-old female patient presented for a comprehensive eye exam to optimize her vision. She reported she had been followed by a retina specialist for AMD for many years. Additionally, she said her sister was diagnosed with a macular condition that significantly limited her vision, though the patient was unclear of the exact condition. The patient and her sister were currently using a retina specialist-recommended AREDS 2 supplement.

The patient’s BCVA during this visit was 20/20-1 OU. All chair skills and IOP measurements were normal. The anterior segment exam was also normal, aside from the expected findings of 2+ nuclear sclerotic cataract OU.

The patient’s retinal exam revealed multiple bilateral linear, reticular-shaped hypopigmented retinal lesions extending from the macula throughout part of the posterior pole (Figure 1). These findings were inconsistent with the classic appearance of AMD in that the lesions were not limited to the macula, no drusen were present, and her vision was remarkably good.

Macular OCT imaging was performed, confirming the lack of classic drusen visualized in AMD (Figure 2). The patient was educated on all findings and was recommended to have genetic testing performed for the diagnosis of a retinal dystrophy.

The Inherited Retinal Disorders Panel was ordered through one of the testing companies, and an oral swab was sent out for analysis. The genetic test identified pathogenic variants in the ABCA4 and TYR genes, which are associated with late-onset Stargardt disease.⁸ In this case, the testing provided the patient with concrete information regarding her health and visual prognosis and highlighted the potential genetic risk for family members, given her sister’s history of unexplained macular disease. It was recommended that the patient’s sister also have genetic testing performed to provide a clearer understanding of her retinal condition. We have not yet heard the sister’s outcome.

COUNSEL PATIENTS

Prior to ordering genetic testing, patients should be counseled on what the testing may reveal. This is because a positive result can create emotional and psychological stress. As an example, genetic testing may influence reproductive decision-making. For this reason, it may be optimally ethical to delay predictive genetic testing on a child for adult-onset ocular diseases until the child can participate in that decision.

Although genetic testing is essential for the diagnosis of many conditions, it does not always guarantee a clear answer. Identification of pathogenic or benign genetic variants is generally the main goal, but variants of uncertain significance can leave both the patient and the provider with questions regarding prognosis. As more tests become available and more genes are sequenced, the frequency of these variants continues to increase.³ Clinicians must establish clear expectations with patients prior to testing to minimize confusion and support informed decision-making.

Counseling patients on how their genetic information may be used is also essential. Genetic testing performed through healthcare providers is protected by the Health Insurance Portability and Accountability Act (HIPAA), and the Genetic Information Nondiscrimination Act (GINA) prohibits health insurers and employers from using genetic information in coverage or employment decisions.⁴ Genetic data shared for research are typically deidentified and subject to additional privacy safeguards. In contrast, direct-to-consumer genetic testing may not be covered by HIPAA or GINA, with the collection and sharing of genetic data governed by company policies, which may have different privacy protections.

Counseling a patient prior to genetic testing may sound like: “Genetic testing can provide information about the cause or risk of certain conditions, but sometimes results can be unexpected, uncertain, or difficult to interpret. Testing may show that you carry a condition that could have implications for relatives, including future offspring. Your genetic information and results are protected by privacy laws and will only be shared with the healthcare professionals involved in your care. We can review the results with you and discuss what they may mean for you and your family.”

PROVIDE SUPPORTIVE RESOURCES

In addition to providing clear expectations, it is important to connect the patient with genetic counseling resources to ensure they understand the full scope of what their testing means and have adequate support as they navigate their diagnosis. Foundation Fighting Blindness (My Retina Tracker Genetic Testing Program) and the National Eye Institute (National Society of Genetic Counselors) connect patients to genetic counselors.

Beyond referral to a genetic counselor, support may also include mental health specialists, such as a psychiatrist, to assist the patient in coping with a new or uncertain diagnosis. Advocacy groups, such as Retina International (https://retina-international.org), can also provide support and a sense of community for those affected.

Further, low vision specialists can assist in maximizing the use of remaining vision. Optometrists can consider having an information sheet with these resources to provide to patients when needed. Collaboration across medical specialties provides full-scope, comprehensive care for all patients.

REFER FOR TREATMENT/CLINICAL TRIALS

Genetic testing results can, in some cases, identify eligibility for targeted therapies. At this time, there are two FDA-approved gene therapies that address ocular conditions. Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics) is a one-time subretinal injection that delivers functional copies of the RPE65 gene to patients who have Leber congenital amaurosis and retinitis pigmentosa.⁵ This injection restores the biochemical “visual cycle” that RPE65 mutations disrupt, so that surviving rods and cones can become more responsive to light. Encelto (revakinagene taroretcel-lwey, Neurotech Pharmaceuticals) is an intravitreal implant that contains genetically modified retinal pigment epithelial cells engineered to produce ciliary neurotrophic factor for neuroprotective purposes to delay photoreceptor degeneration in patients who have macular telangiectasia type 2.⁶

There are many clinical trials currently underway for therapies for other genetic conditions, such as achromatopsia, Stargardt disease, X-linked retinoschisis, and more.⁷Available clinical trials can be found on clinical trials.gov.

AN APPRECIATED SERVICE

Although such cases may not be encountered daily, genetic testing remains an important diagnostic tool that eyecare providers should keep in mind. Thoughtful and responsible use of genetic testing, in addition to appropriate professional recommendations and ethical considerations, can reinforce clinical decision-making and enhance patient-centered care.